Metabolic diseases represent a serious public health concern worldwide. Obese and overweight individuals account for half or more of the population of the United States, and the incidence of obesity has risen at an alarming rate over the two decades. Compared to lean individuals, overweight persons are susceptible to an array of disorders, including heart disease, high blood pressure, Type II diabetes, insulin resistance, stroke, and others (Must et al., 1999). The etiology of excess weight gain is complex and incompletely understood. In persons developing overweight or obese conditions, environmental and genetic factors underlie an imbalance between appetite/caloric intake and energy expenditure. Thus, novel strategies that improve energy balance through modulation of appetite and/or metabolic rate are useful to correct relevant diseases including obesity-related disorders such as insulin resistance, diabetes, circulatory system anomalies, etc.
Strategies to thwart excessive adipose tissue growth and accretion may also help in the treatment of obesity, or in the treatment of other diseases associated with the presence of inappropriately high amounts of this tissue globally or locally (i.e., lipomas, phaeochromocytomas, hibernomas). Innovative clinical treatments, including improving the circulating or tissue levels of triglycerides, cholesterol, glucose, insulin, leptin or other metabolically-relevant molecules, that help normalize one or more of the altered factors concomitant with metabolic derangement would also have tremendous value.
Increased risks of mortality and morbidity associated with perturbations of metabolism are not confined to the obese, overweight, or diabetic states, however. Cachexia, the loss of appetite, leading to fewer calories eaten in comparison to caloric requirements, is a feature of numerous disease states, including certain cancers, some viral infections (i.e., acquired immunodeficiency syndrome, AIDS), or bacterial infections (i.e., during some stages of sepsis), and can result in loss of fat mass and lean body mass. Furthermore, conditions in which energy expenditure is abnormally elevated can benefit from novel modalities that modulate metabolism. In severe burns, for instance, the metabolic rate can rise almost two-fold, malting administration of appropriate nutrition a tremendous challenge (Goldstein and Elwyn, 1989; Kinney et al., 1970). The clinical prognosis is poor for patients who drift into negative energy balance in such disease states (Tisdale, 1997), or in those persons suffering from excessive fat loss body-wide or regionally (i.e., lipoatrophic and lipodystrophic disorders). Treatment of metabolic disease may be in part effected through the innovative use of certain molecules as drugs or as targets of pharmaceutical, nutritional, or other interventions.
There is also a pressing need to discover molecules that may be used in creative diagnostic and/or predictive strategies associated with metabolic disease. For instance, alterations in the expression of certain genes and proteins may underlie or mark the progression of metabolic diseases associated with adipose tissue amount or adipose tissue physiology, such as obesity, lipoatrophic diseases, etc. Thus, analysis of the expression of certain genes and proteins in afflicted patients compared to a healthy population will assist in unraveling the etiology and/or progression level of their disease, thereby helping in the design of effective therapeutic and preventive strategies. Healthy patients may be screened for expression in cases in which expression is altered prior to the onset of disease, thus allowing for pre-emptive treatments that can limit metabolic disease progression. Furthermore, changes in the gene or protein sequences (and/or other alterations such as methylation, acylation, phosphorylation, etc.) in certain populations may be associated with disease or risk toward developing disease. This illustrates the need to discover new genes and proteins relevant to metabolic disorders and whose sequences or alterations lead to biological changes that predispose to metabolic disease, or are in fact predictive of the progression of disease. Finally, knowledge of such unique genes and proteins at the expression or activity level will enable tracking of the efficacy of therapeutic modalities designed to treat metabolic diseases; as well as, the use of expression and sequence analysis to monitor or predict the outcome of other diseases associated with excessive fat accretion, or those associated with abnormal fat loss. Discovery of fat cell-abundant genes and proteins are especially attractive in this regard.
Thus an embodiment of the invention describes γ-synuclein as an adipocyte (fat cell) abundant factor, and use of the protein and γ-synuclein-encoding nucleic acids in treating or preventing metabolic diseases in humans that are associated with or responsive to fat tissue amount and/or adipose tissue functions. Novel evidence for an important role for γ-synuclein in modifying adipose tissue function is presented. The white and brown adipose tissue of mammals are known to play a central role in energy storage and metabolic signaling, thus impacting appetite, metabolic rate, and energy balance, and the white adipose tissue also implicated as an important inflammatory tissue. Based on its adipose-abundance and its clear induction during the white adipocyte differentiation process, responsiveness of its expression in adipocytes to agonism of the known metabolic regulator protein peroxisome proliferator activated receptor (PPAR), and shifted adipose tissue expression level in obese human subjects, γ-synuclein appears to have important utility as a drug and drug target to treat or prevent metabolic disease and related disorders, including those characterized by excessive adipose accretion or abnormally low adipose stores. Furthermore, γ-synuclein mRNA or protein abundance in patient tissues may be used to diagnose, monitor, and assess treatment efficacy of metabolic disorders associated with adiposity or γ-synuclein activity. Finally, γ-synuclein protein or nucleotide sequence polymorphisms, or distinct modifications of the gene, mRNA, or protein by non-genomic factors such as methylation, acylation, etc., may be used as predictive biomarkers of metabolic disease risk or disease progression.
Described herein is the correlation between expression patterns of γ-synuclein and leptin in fat cells, coupled to a protein chaperone role of γ-synuclein reported in other cell types, supporting the novel concept that γ-synuclein activity is associated with factors that regulate net leptin expression/production/secretion and/or leptin protein folding. Considering the well-established role of leptin in modulating whole-body metabolism and obesity phenotypes, the association between leptin and γ-synuclein indicates that one role of the latter is to regulate net activity of leptin and hence, would regulate leptin-associated biological pathways. Thus, γ-synuclein mRNA or protein abundance in patient tissues may be used to diagnose, monitor, and assess treatment efficacy of disorders associated with dysfunctional leptin expression, secretion, and/or activity.
In addition, γ-synuclein protein or nucleotide sequence polymorphisms, or distinct modifications of the gene, mRNA, or protein by non-genomic factors such as methylation, acylation, etc., may be used as predictive biomarkers of disease risk or disease progression for conditions related to altered leptin availability or activity.